1. Field of the Invention
The present invention relates to stabilized topical pharmaceutical preparations. More specifically the present invention relates to a stabilized topical pharmaceutical preparation, based on the solubilization of a eutectic mixture of local anesthetic agents, in base form, which when combined in the presence of a surfactant and water produces a single phase hydrated polymer, to be used in obtaining topical anesthesia and also relates to a stabilized pharmaceutical preparation which is compatible with open wounds.
2. Discussion of the Background
Since their initial discovery, the formulation of topical pharmaceutical preparations have been investigated to address specific stability problems which arise with specific pharmaceutical agents.
Special stability problems have been noted in the area of local anesthetics and antimicrobial creams. In both instances, the availability of a stable preparation, with good bioavailability, has been lacking, despite the obvious need for such preparations. To date, the stability problems with each of these preparations has not been completely solved, necessitating preparation of such topical preparations shortly before use. This problem places a huge burden on hospital pharmacies, a burden which could be eased if a storage stable preparation could be developed.
Attempts have been made at obtaining stable topical anesthesia. One attempt involved the production of an anesthetically active film comprised of lidocaine in crystallized form. The problem with a solid carrier of this type is the inaccuracy in the dosage of anesthetic present in the carrier at any given time.
Further attempts have been made utilizing local anesthetically active compounds, in base form, while these compounds remain in crystalline form. The result has been that the desired anesthetic effect does not result. An attempt has also been made at a homogenous oil comprised of different anesthetic agents in base form. In such cases the active agents are not present in water soluble form. When placed in water, an oil in water emulsion results which is not stable or homogenous in composition.
Broberg et al (U.S. Pat. No. 4,529,601) report a pharmacologically active preparation of local anesthetics in the form of a eutectic mixture of two topical anesthetics, where one anesthetic has a melting point of 30.degree. to 50.degree. C. and the other has a melting point of above 30.degree. C. The eutectic mixture is then administered in the form of an aqueous emulsion of an emulsifying agent and water. The disadvantage of this topical anesthetic is the general instability of emulsion preparations, which leads to inaccurate dosing when applied.
Specific problems in stability have also been noted in the area of topical antimicrobial and anti-fungal preparations. Such preparations are essential to the survival of severe burn victims.
In treating burn victims, it is typical to treat the open wounds with antimicrobial and anti-fungal agents such as a nitrofuran, polymyxin, nystatin or a mixture thereof. In the case of treating open wounds, such as burns, the carrier must also be non-damaging to the tissue. Polyoxyalkylene based carriers, such as a Poloxamer (Pluronic F-68 by BASF-Wyandott), are suitable based on their tissue non-toxicity.
However, pharmaceutical gels based on Poloxamer carriers are subject to low temperature phase separation, which decreases the usefulness of the preparation. Previous attempts have been made at obtaining stability in a Poloxamer gel, however, the results have been unsatisfactory. These attempts have involved increasing aeration during manufacturing, varying antimicrobial agents, and increasing temperature during manufacture. To date, unsatisfactory low temperature stability has been observed, as evidenced by the data in the table below, in which Poloxamer based preparations were prepared:
Time to phase transition of antimicrobial burn gel
______________________________________ TIME (minutes) PRODUCT COMBINATION 32-35.degree. F. ______________________________________ Nystatin 12 Polymyxin 10 Nitrofurantoin 13 Nystatin/Polymyxin 13 Nystatin/Nitrofurantoin 12 Polymyxin/Nitrofurantoin 10 Nystatin/Polymyxin/ 10 Nitrofurantoin ______________________________________
The problem with these gels is that a phase transition occurred at low temperatures resulting in inaccuracy of the dosage of antimicrobial agents due to their settling to the bottom of the container. Further attempts have been made utilizing bases other than Poloxamer and antimicrobial agents. Numerous problems with these preparations include the need to mechanically remove the preparation prior to a second application (silvadene), poor release of antimicrobial agents from the base (i.e poor bioavailability), damage to new tissue and lack of penetration in eschar (Vaseline based).
The purpose of this invention is to solubilize high concentrations of local anesthetic agents in base form to produce a stable hydrated polymer which can then be applied to the intended surface.
The purpose of this invention is also to provide a stabilized Poloxamer base to produce a stable gel to which antimicrobial agents and other pharmaceutical agents, can then be added.